The morphinan alkaloids represent a family of structurally-related products of great medicinal importance. Particular morphinan compounds of pharmaceutical relevance include, for example, codeine, hydrocodone, hydromorphone, morphine, nalbuphine, nalmefene, naloxone, naltrexone, oxycodone, and oxymorphone. Generally, these compounds are analgesics, which are used extensively for pain relief in the field of medicine due to their action as opiate receptor agonists. However, nalmefene, naloxone, naltrexone, and naltrexone methyl bromide are opiate receptor antagonists, and are used for reversal of narcotic/respiratory depression due to opiate receptor agonists, as addiction therapies, and to reverse other undesirable side effects of opiate agonist use, such as severe constipation.
Morphinan compounds and analogs thereof typically have a ring structure generally corresponding to Formula (1):

Various methods are known for the synthesis of morphinan compounds corresponding to Formula (1). Conventional methods used in the commercial production of morphinan compounds typically involve the extraction of opium alkaloids from poppies (papaver somniferum). Generally speaking, these processes involve the extraction of the alkaloids from opium in a liquid, precipitation of the alkaloids, separation of the raw alkaloids (e.g., morphine and secondary alkaloids such as papaverine, codeine, and thebaine), and purification of the various alkaloids, optionally followed by semi-synthesis steps to produce particular morphinan compounds. See, for example, Barbier, A., “The Extraction of Opium, Twenty-five years of commercial experience in the treatment of opium,” Ann. Pharm. Franc., 1947, 5, 121-40; Barbier, A., “The Extraction of Opium Alkaloids,” Bull. Narcotics, 1950, vol. 3, 22-29; Heumann, W, “The Manufacture of Alkaloids from Opium,” Bull. Narcotics, 1957, vol. 2, 34-40; Lednicer and Mitscher, Organic Chemistry of Drug Synthesis, chapter 15, (Wiley 1977); French Patent No. 1,000,543 to Penau et al.; British Patent No. 713,689 to Wood et al.; and U.S. Pat. No. 2,009,181 to Kábay.
Synthetic methods for producing various morphinan compounds are also known. These methods commonly utilize 3-methoxy-phenylethylamine as a starting material and include a Grewe cyclization step. For example, in U.S. Pat. No. 4,368,326, Rice discloses a process for preparing a nordihydrothebainone (e.g., 1-bromo-N-formylnordihydrothebainone) from a β,γ-hexahydroisoquinolone (e.g., 1-(2′-bromo-4′-methoxy-5′-hydroxybenzyl)-2formyl-1,3,4,5,7,8-hexahydroquinolin-6-one) by Grewe cyclization catalyzed using a super acid catalyst alone or with a combination of an ammonium fluoride complex and trifluoromethanesulfonic acid.
Many pharmaceutically desirable morphinan compounds and analogs thereof have a ketone group on the C-ring of Formula (1) and a saturated bond between the two carbon atoms positioned α and β to the ketone on the C-ring of Formula (1). According to the common nomenclature, the ketone is present on the C(6) carbon atom, with the α and β carbon atoms being the C(7) and C(8) positions (see, e.g., Formula (1)). Thus, these compounds may be referred to as morphinan-6-one compounds. Various processes for producing morphinan-6-one compounds are known, many of which involve some form of catalytic hydrogenation of α,β-unsaturated ketone intermediate compounds at particular points in the process. Commonly used catalysts include, for example, palladium and platinum. For example, in U.S. Pat. No. 6,177,567 to Chiu et al., 14-hydroxycodeinone (an α,β-unsaturated ketone compound) is converted to oxycodone by hydrogenating the α,β-unsaturation using conventional methods such as reduction by diphenylsilane and Pd(Ph3P)/ZnCl2, or with sodium hypophosphite in conjunction with a Pd/C catalyst in aqueous acetic acid, or by Pd/C catalytic transfer hydrogenation.
While these and other methods of reducing or removing the α,β-unsaturation are generally effective, α,β-unsaturated ketone compounds may persist as impurities in the final products of desirably α,β-saturated morphinan-6-one products, such as oxycodone. Additionally, known hydrogenation methods may tend to undesirably reduce the ketone as well as reducing or removing the α,β-unsaturation. Further, these and other hydrogenation methods are not normally capable of efficiently and economically reducing the levels of 7,8-unsaturation to below 10 to 100 parts per million, or less.
Some α,β-unsaturated ketone compounds show mutagenic activity in certain tests. Therefore, a need persists for processes for preparing highly pure morphinan-6-one products having a relatively low concentration of α,β-unsaturated ketone compounds present as impurities therein.